Showing papers by "Fumihiko Matsuda published in 2019"

Identification of type 2 diabetes loci in 433,540 East Asian individuals

Abstract: Meta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1 , PTF1A , SIX3 , ALDH2 , a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1 , in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.

Hyperglycemia in non-obese patients with type 2 diabetes is associated with low muscle mass: The Multicenter Study for Clarifying Evidence for Sarcopenia in Patients with Diabetes Mellitus.

Abstract: AIMS/INTRODUCTION Hyperglycemia is a risk factor for sarcopenia when comparing individuals with and without diabetes. However, no studies have investigated whether the findings could be extrapolated to patients with diabetes with relatively higher glycemic levels. Here, we aimed to clarify whether glycemic control was associated with sarcopenia in patients with type 2 diabetes. MATERIALS AND METHODS Study participants consisted of patients with type 2 diabetes (n = 746, the average age was 69.9 years) and an older general population (n = 2,067, the average age was 68.2 years). Sarcopenia was defined as weak grip strength or slow usual gait speed and low skeletal mass index. RESULTS Among patients with type 2 diabetes, 52 were diagnosed as having sarcopenia. The frequency of sarcopenia increased linearly with glycated hemoglobin (HbA1c) level, particularly in lean individuals (HbA1c <6.5%, 7.0%, ≥6.5% and <7.0%: 18.5%; HbA1c ≥7.0% and <8.0%: 20.3%; HbA1c ≥8.0%: 26.7%). The linear association was independent of major covariates, including anthropometric factors and duration of diabetes (HbA1c <6.5%: reference; ≥6.5% and <7.0%: odds ratio [OR] 4.38, P = 0.030; HbA1c ≥7.0% and <8.0%: 4.29, P = 0.024; HbA1c ≥8.0%: 7.82, P = 0.003). HbA1c level was specifically associated with low skeletal mass index (HbA1c ≥8.0%: OR 5.42, P < 0.001) rather than weak grip strength (OR 1.89, P = 0.058) or slow gait speed (OR 1.13, P = 0.672). No significant association was observed in the general population with a better glycemic profile. CONCLUSIONS Poor glycemic control in patients with diabetes was associated with low muscle mass.

Advanced Glycation End Product Accumulation Is Associated With Low Skeletal Muscle Mass, Weak Muscle Strength, and Reduced Bone Density: The Nagahama Study.

Abstract: BACKGROUND The accumulation of advanced glycation end product (AGE) might exert deleterious effects on musculoskeletal properties. Our study aims to clarify this possible association in a large general population. METHODS This study investigated a general population of 9,203 patients (mean age, 57.8 years). Skeletal muscle mass was measured by bioelectrical impedance analysis, whereas accumulation of AGEs was assessed by skin autofluorescence (SAF-AGE). The muscle strength of upper and lower limbs and usual gait speed were measured in a portion of older (≥60 years of age) participants (n = 1,934). The speed of sound (SOS) in the calcaneal bone was assessed via a quantitative ultrasound technique. RESULTS In the total population, the frequency of low skeletal muscle mass linearly increased with the SAF-AGE quartiles (Q1: 14.2%, Q2: 16.1%, Q3: 21.1%, Q4: 24.8%; p < .001), and this association was independent of covariates including glycemic traits (Q4: odds ratio [OR] = 1.48, p < .001). The association between the highest SAF-AGE quartile and low skeletal muscle mass remained significant in the older subpopulation (OR = 1.85, p = .002). A similar but weak association was observed for low SOS (Q1: 8.9%, Q2: 8.3%, Q3: 10.4%, Q4: 12.2%; p < .001). Similar inverse associations were also observed with grip strength (OR = 1.98, p = .003), hip flexion strength (OR = 1.50, p = .012), and hip abduction strength (OR = 1.78, p = .001), but not with usual gait speed. CONCLUSION Accumulation of AGEs might be a deleterious factor for musculoskeletal properties.

Genome-wide association analyses identify two susceptibility loci for pachychoroid disease central serous chorioretinopathy

Abstract: The recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD. Yoshikatsu Hosoda et al. present a genome-wide association study in Japanese and European cohorts, identifying genes related to central serous chorioretinopathy pathogenesis. They report two novel susceptibility loci, one of which is a known risk allele for age-related macular degeneration.

IgG4-related disease in the Japanese population: a genome-wide association study

Abstract: Summary Background IgG4-related disease is a newly recognised immunopathological entity that includes autoimmune pancreatitis, IgG4-related sialadenitis, and IgG4-related kidney disease. To understand the genetic landscape of IgG4-related disease, we did a genome-wide association study. Methods We did a genome-wide association study of Japanese individuals, initially screening 857 patients with IgG4-related disease at 50 Japanese research institutions and DNA samples from 2082 healthy control participants from the Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience. From Oct 27, 2008, to July 22, 2014, we enrolled 835 patients and used data from 1789 healthy participants. Only patients with confirmed diagnosis of IgG4-related disease according to the international diagnostic criteria were included. Genotyping was done with the Infinium HumanOmni5Exome, HumanOmni2.5Exome, or HumanOmni2.5 Illumina arrays, and genomic distributions were compared between case and control samples for 958 440 single nucleotide polymorphisms. The HLA region was extensively analysed using imputation of HLA alleles and aminoacid residues. Fine mapping of the FCGR2B region was also done. Associations between clinical manifestations of disease and the genetic variations identified in these two genes were examined. Findings We identified the HLA-DRB1 (p=1·1×10−11) and FCGR2B (p=2·0×10−8) regions as susceptibility loci for IgG4-related disease. We also identified crucial aminoacid residues in the β domain of the peptide-binding groove of HLA-DRB1, in which the seventh aminoacid residue showed the strongest association signal with IgG4-related disease (p=1·7×10−14), as has been reported with other autoimmune diseases. rs1340976 in FCGR2B showed an association with increased FCGR2B expression (p=2·7×10−10) and was in weak linkage disequilibrium with rs1050501, a missense variant of FCGR2B previously associated with systemic lupus erythematosus. Furthermore, rs1340976 was associated with the number of swollen organs at diagnosis (p=0·011) and IgG4 concentration at diagnosis (p=0·035). Interpretation Two susceptibility loci for IgG4-related disease were identified. Both FCGR2B and HLA loci might have important roles in IgG4-related disease development. Common molecular mechanisms might underlie IgG4-related disease and other immune-related disorders Funding The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, and Kyoto University Grant for Top Global University Japan Project.

Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection

Abstract: The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel-significant associations at 5q14 with the lead single nucleotide polymorphism (SNP) rs59661306 (P = 2.4 × 10-11) and at 7p11 with the lead SNP rs7457728 (P = 1.2 × 10-8). In 5q14, the chromatin region of the GWAS-significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain-containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development.

PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes.

Abstract: Objectives Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice. Methods We conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant. Results We found a total of 14 significant loci, which included rs2582511 in AHNAK2/PLD4 recently reported in a Chinese study and a novel locus of rs143181706 in MAMLD1 (p=7.9×10−11 and 3.7×10–8, respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immune-related cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and anti-dsDNA antibody. Conclusions We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.

NARD: whole-genome reference panel of 1779 Northeast Asians improves imputation accuracy of rare and low-frequency variants

Abstract: Here, we present the Northeast Asian Reference Database (NARD), including whole-genome sequencing data of 1779 individuals from Korea, Mongolia, Japan, China, and Hong Kong. NARD provides the genetic diversity of Korean (n = 850) and Mongolian (n = 384) ancestries that were not present in the 1000 Genomes Project Phase 3 (1KGP3). We combined and re-phased the genotypes from NARD and 1KGP3 to construct a union set of haplotypes. This approach established a robust imputation reference panel for Northeast Asians, which yields the greatest imputation accuracy of rare and low-frequency variants compared with the existing panels. NARD imputation panel is available at https://nard.macrogen.com/ .

Untargeted Mass Spectrometry Lipidomics identifies correlation between serum sphingomyelins and plasma cholesterol

Abstract: Lipoproteins are major players in the development and progression of atherosclerotic plaques leading to coronary stenosis and myocardial infarction. Epidemiological, genetic and experimental observations have implicated the association of sphingolipids and intermediates of sphingolipid synthesis in atherosclerosis. We aimed to investigate relationships between quantitative changes in serum sphingolipids, the regulation of the metabolism of lipoproteins (LDL, HDL), and endophenotypes of coronary artery disease (CAD). We carried out untargeted liquid chromatography – mass spectrometry (UPLC-MS) lipidomics of serum samples of subjects belonging to a cross-sectional study and recruited on the basis of absence or presence of angiographically-defined CAD, and extensively characterized for clinical and biochemical phenotypes. Among the 2998 spectral features detected in the serum samples, 1328 metabolic features were significantly correlated with at least one of the clinical or biochemical phenotypes measured in the cohort. We found evidence of significant associations between 34 metabolite signals, corresponding to a set of sphingomyelins, and serum HDL cholesterol. Many of these metabolite associations were also observed with serum LDL and total cholesterol levels but not as much with serum triglycerides. Among patients with CAD, sphingolipids in the form of sphingomyelins are directly correlated with serum levels of lipoproteins and total cholesterol. Results from this study support the fundamental role of sphingolipids in modulating lipid serum levels, highlighting the importance to identify novel targets in the sphingolipid metabolic pathway for anti-atherogenic therapies.

Low back pain precedes the development of new knee pain in the elderly population; a novel predictive score from a longitudinal cohort study

Abstract: To investigate the association between knee pain and risk factors including low back pain and to develop a score to predict new knee pain in an older population, using population-based longitudinal cohort data. We collected a questionnaire on self-reported knee pain and demographic data in a systematic manner from community residents aged ≥ 50 years twice, at baseline, and after 5 years. Multivariate logistic regression analyses were performed to investigate the association between knee pain and risk factors and to build a predictive model that would enable calculation of the risk of the development of knee pain within 5 years. The model is presented in the form of score charts. A total of 5932 residents aged ≥ 50 years from the cohort of 9764 that completed the first questionnaire were enrolled in the second survey. After exclusions, paired data for the two time points an average of 5.4 years apart were analyzed for 4638 participants. Multivariate analyses showed older age, female sex, higher BMI, weight increase, lower mental health score, and higher back pain/disability score were independent risk factors for knee pain. The predictive score comprised six factors: age, sex, BMI, weight increase, mental health, and low back pain/disability. The risk of developing knee pain ranged from 11.0 to 63.2% depending on the total score. This study demonstrated a significant association between knee and low back pain/disability along with other risk factors. The score we developed can be used to identify a population without any imaging modality who are at high risk of developing knee pain.

Genetic basis for plasma amino acid concentrations based on absolute quantification: a genome-wide association study in the Japanese population.

Abstract: To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography–mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2 and PKD1L2, were identified. SLC7A2 was associated with the plasma levels of arginine and ornithine, and PKD1L2 with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1 gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.

Association of the spot urine sodium-to-potassium ratio with blood pressure is independent of urinary Na and K levels: The Nagahama study.

Abstract: The sodium-to-potassium ratio (Na/K) of a urine sample is a simple index of salt loading. To practically use Na/K, we aimed to determine whether the Na/K value affects blood pressure (BP) at any age, irrespective of urinary Na and K levels. We analyzed a dataset of the general population (the Nagahama study), including baseline and second-visit measurements performed 5 years after the baseline. Spot urine samples were used for Na/K assessments. A total of 18,505 observations were analyzed using a linear mixed model, including the measurement term as a random effect. Urinary Na/K values showed a positive association with BP. When the highest quartile of Na/K was further divided by the urinary Na/creatinine (Cre) and K/Cre levels, the high-Na/Cre (3.58) and high-K/Cre (0.75) (Na/K = 4.80) groups, as well as the low Na/Cre (1.23) and low-K/Cre (0.26) (Na/K = 4.87) groups, exhibited similar effects on systolic BP (6.82 mmHg [95% CI: 5.72–7.92] and 6.63 mmHg [95% CI: 5.35–7.91], respectively). A similar association was observed in other Na/K quartiles. The positive association of Na/K and Na/Cre with BP was steeper in the older groups, while the inverse association of K/Cre was predominant in the younger population. The results of the multivariate analysis identified interaction terms between age and Na/K, Na/Cre and K/Cre as significant determinants for SBP. The positive association of urinary Na/K with BP was independent of the urinary Na and K levels. The association between Na/K and BP may not be uniform across ages by decade.

pJRES Binning Algorithm (JBA): a new method to facilitate the recovery of metabolic information from pJRES 1H NMR spectra.

Abstract: MOTIVATION Data processing is a key bottleneck for 1H NMR-based metabolic profiling of complex biological mixtures, such as biofluids. These spectra typically contain several thousands of signals, corresponding to possibly few hundreds of metabolites. A number of binning-based methods have been proposed to reduce the dimensionality of 1 D 1H NMR datasets, including statistical recoupling of variables (SRV). Here, we introduce a new binning method, named JBA ("pJRES Binning Algorithm"), which aims to extend the applicability of SRV to pJRES spectra. RESULTS The performance of JBA is comprehensively evaluated using 617 plasma 1H NMR spectra from the FGENTCARD cohort. The results presented here show that JBA exhibits higher sensitivity than SRV to detect peaks from low-abundance metabolites. In addition, JBA allows a more efficient removal of spectral variables corresponding to pure electronic noise, and this has a positive impact on multivariate model building. AVAILABILITY AND IMPLEMENTATION The algorithm is implemented using the MWASTools R/Bioconductor package. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy.

Abstract: Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10-7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10-8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10-27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.

Legacy Data Confounds Genomics Studies

Abstract: Recent reports have identified differences in the mutational spectra across human populations. While some of these reports have been replicated in other cohorts, most have been reported only in the 1000 Genomes Project (1kGP) data. While investigating an intriguing putative population stratification within the Japanese population, we identified a previously unreported batch effect leading to spurious mutation calls in the 1kGP data and to the apparent population stratification. Because the 1kGP data is used extensively, we find that the batch effects also lead to incorrect imputation by leading imputation servers and a small number of suspicious GWAS associations. Lower-quality data from the early phases of the 1kGP thus continues to contaminate modern studies in hidden ways. It may be time to retire or upgrade such legacy sequencing data.

Lifestyle habits associated with nocturnal urination frequency: The Nagahama study

Abstract: BACKGROUND Nocturia is a risk factor for poor quality of life and increased mortality. This study was aimed to clarifying dietary habits, eating behaviors, and sleep characteristics associated with nocturia to identify modifiable lifestyle factors for nocturia. METHODS This cross-sectional study included 5683 community residents (64.5 ± 7.7 years old). The frequency of nocturnal urination was recorded for 1 week using a sleep diary. The frequency of food intake, unfavorable eating behaviors, and sleep characteristics that may have influence on salt intake and wasting were obtained using a structured questionnaire. RESULTS The frequency of nocturnal urination was increased with age (β = .312, P < .001). Other basic factors associated with the frequency were the male sex (β = .090), hypertension (β = .038), sleep apnea (β = .030), B-type natriuretic peptide level (β = .089), and spot urine sodium excretion (β = -.058). Dietary factors independently associated with nocturnal urination frequency were coffee (≥1 time/day: β = -.059, P < .001) and green vegetable consumption (≥1 time/week: β = -.042, P = .001), whereas habitual intake of dairy products, miso soup, and alcohol were not associated with urination frequency. Later bedtime was inversely associated with nocturnal urination frequency independent of sleep duration (before 23:00: β = -.096; before 24:00: β = -.225; after midnight: β = -.240; all P < .001). CONCLUSION Coffee and green vegetable consumption and later bedtime but not sleep duration are lifestyle factors associated with nocturnal urination frequency.

Frequent nocturnal urination in older men is associated with arterial stiffness: The Nagahama study.

Abstract: Nocturia in older adults has been reported to be a risk factor for cardiovascular outcomes, and the stiffening of large arteries might be an underlying mechanism. To clarify the possible association between nocturia and arterial stiffness, we analyzed a dataset from the Japanese general population. Study participants consisted of 5928 community residents (mean age: 60.0 ± 11.8 years). The frequency of nocturnal urination was recorded for 1 week using a sleep diary. Arterial stiffness was assessed by brachial-to-ankle pulse wave velocity (baPWV). Sleep blood pressure was measured automatically at 0000, 0200, and 0400 hours by wearing a cuff on the upper arm during sleep. The mean baPWV was 1278 ± 227 cm/s. The frequency of nocturnal urination showed a linear positive association with baPWV (P 1.5 times/night (corresponding to a ≥ 2 times/night frequency obtained by the questionnaire) and baPWV remained significant after adjusting for major covariates, including office blood pressure (β = 0.051, P < 0.001) and sleep blood pressure (β = 0.040, P < 0.001). This association was more prominent in men (β = 0.069, P < 0.001) than in women (β = 0.023, P = 0.013), particularly in older (β = 0.068, P = 0.006) compared with younger (β = 0.029, P = 0.270) men. Frequent nocturnal urination was independently associated with baPWV in older men. Nocturia may be a marker for cardiovascular disease risks that cannot be assessed by conventional risk factors such as blood pressure.

Whole-genome reference panel of 1,781 Northeast Asians improves imputation accuracy of rare and low-frequency variants

Abstract: Genotype imputation using the reference panel is a cost-effective strategy to fill millions of missing genotypes for the purpose of various genetic analyses. Here, we present the Northeast Asian Reference Database (NARD), including whole-genome sequencing data of 1,781 individuals from Korea, Mongolia, Japan, China, and Hong Kong. NARD provides the genetic diversities of Korean (n=850) and Mongolian (n=386) ancestries that were not present in the 1000 Genomes Project Phase 3 (1KGP3). We combined and re-phased the genotypes from NARD and 1KGP3 to construct a union set of haplotypes. This approach established a robust imputation reference panel for the Northeast Asian populations, which yields the greatest imputation accuracy of rare and low-frequency variants compared with the existing panels. Also, we illustrate that NARD can potentially improve disease variant discovery by reducing pathogenic candidates. Overall, this study provides a decent reference panel for the genetic studies in Northeast Asia.

LAVENDER: latent axes discovery from multiple cytometry samples with non-parametric divergence estimation and multidimensional scaling reconstruction

Abstract: Computational cytometry methods are now frequently used in flow and mass cytometric data analyses. However, systematic bias-free methodologies to assess inter-sample variability have been lacking, thereby hampering efficient data mining from a large set of samples. Here, we devised a computational method termed LAVENDER (latent axes discovery from multiple cytometry samples with nonparametric divergence estimation and multidimensional scaling reconstruction). It measures the Jensen-Shannon distances between samples using the k-nearest neighbor density estimation and reconstructs samples in a new coordinate space, called the LAVENDER space. The axes of this space can then be compared against other omics measurements to obtain biological information. Application of LAVENDER to multidimensional flow cytometry datasets of 301 Japanese individuals immunized with a seasonal influenza vaccine revealed an axis related to baseline immunological characteristics of each individual. This axis correlated with the proportion of plasma cells and the neutrophil-to-lymphocyte ratio, a clinical marker of the systemic inflammatory response. The same method was also applicable to mass cytometry data with more molecular markers. These results demonstrate that LAVENDER is a useful tool for identifying critical heterogeneity among similar, yet different, single-cell datasets.

National platform for Rare Diseases Data Registry of Japan.

Abstract: Introduction In Japan, there are approximately 300 projects conducting research on rare diseases supported by the Ministry of Health, Labour and Welfare of Japan (MHLW) and the Japan Agency for Medical Research and Development (AMED). Diverse data, including clinical, genomic, and sample-related data, are generated by these projects. However, at present, such data are managed individually by each project. This makes it difficult for third parties to ascertain the data generated by projects. Methods Again this background, at the beginning of 2017, the AMED started the National Platform for Rare Diseases Data Registry of Japan (RADDAR-J), whose mission is to construct a cross-sectional data integration platform incorporating projects supported by the AMED and MHLW. RADDAR-J promotes data sharing by the projects in accordance with the data-sharing policy established by the AMED, which classifies data sharing into three categories based on the strategies used to protect the rights of researchers while promoting data sharing. RADDAR-J integrates and analyzes data shared by each project to add value to the resources and promote secondary use by third parties while protecting the rights of the researchers who shared their data. The platform is designed to provide incentives to projects that shared their data by supporting registry construction or genomic analysis to promote data sharing. RADDAR-J also has the function of data identification to securely integrate data originating from the same person. RADDAR-J accelerates clinical research by encouraging each project to utilize a central ethics committee. Results/Conclusion The use of the platform by projects is expected to lead to streamlined data collection, improved quality assurance, improved access to data, and promotion of joint research and the secondary use of shared data. These benefits will accelerate research into diagnosis and treatment technologies and will hopefully lead to improved quality of life for patients with rare diseases.

Population-specific and transethnic genome-wide analyses reveal distinct and shared genetic risks of coronary artery disease

Abstract: To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study (GWAS) of 168,228 Japanese (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,782 CAD cases and 3,148 controls. We detected 9 novel disease-susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a transethnic meta-analysis and discovered 37 additional novel loci. Using the result of the meta-analysis, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European GWAS. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improves clinical characterization of CAD genetics and suggests the utility of transethnic meta-analysis for PRS derivation in non-European populations.

Association of weak hip abduction strength with nocturia in older women: The Nagahama study

Abstract: Aim Nocturia is a common phenomenon in older individuals, and is associated with poor quality of life. Nocturia is a multifactorial disorder, wherein the frailty of skeletal muscles, particularly muscle weakness in the lower trunk and hip regions, might be a risk factor in women. We analyzed a dataset of the general Japanese population to clarify the hypothesis. Methods Study participants included 1207 older women (mean age 67.4 ± 5.2 years). The frequency of nocturnal urination was assessed using a sleep diary for 1 week, and associations with lower muscle strength, skeletal muscle index, sarcopenia and physical performance (one-leg standing time and Timed Up and Go test) were investigated. Results The frequency of nocturnal urination more than one voiding per night was 28.1%; this frequency was inversely associated with hip abduction strength quartiles (Q1: 37.0, Q2: 30.5, Q3: 25.1 and Q4: 19.9%, P 1.5 times/night (corresponding to a ≥2 times/night frequency obtained by questionnaire) was considered as nocturia, logistic regression analysis adjusted for major covariates identified hip abduction strength as an independent inverse determinant of nocturia (odds ratio 0.75, 95% CI 0.52-0.90, P = 0.002). In contrast, no significant association was observed with knee extension (P = 0.322) and hip flexion (P = 0.603) strengths. Physical performance, skeletal muscle index and sarcopenia did not show significant associations with nocturia. Conclusions Weak hip abduction strength might be a factor associated with nocturnal urination frequency in older women. Geriatr Gerontol Int 2019; 19: 1010-1016.

Abstract LB-174: Genome-wide association meta-analysis identifies novelGP2gene risk variants for pancreatic cancer in the Japanese population

Abstract: Pancreatic cancer is one of the most challenging malignancies because of its dismal prognosis, largely unknown etiology, and absence of early detection method. Here we report the results of a meta-analysis of three genome-wide association studies (GWAS) involving 2039 pancreatic cancer cases and 32592 control subjects, which represent the largest sample size in the Japanese population. To complement the SNP-based GWAS, we performed a gene-based GWAS using MAGMA. Given the pleiotropic effects observed for the top variants, we performed a Mendelian randomization (MR) analysis to address the possible causal relationship between type-2 diabetes (T2D) and pancreatic cancer risk, using 82 T2D-related SNPs and 25 hemoglobin A1c (HbA1c)-related SNPs as instrumental variables. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P Citation Format: Yingsong Lin, Masahiro Nakatochi, Hidemi Ito, Yoichiro Kamatani, Hiromi Sakamoto, Hiroshi Ishii, Naoki Sasahira, Makoto Ueno, Naoto Egawa, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Atsushi Shimizu, Takashi Kadowaki, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo. Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-174.

Pcr primer set for hla gene, and sequencing method using same

Abstract: The present invention provides a primer set for use in HLA gene amplification, which contains a primer comprising a nucleotide sequence represented by any one SEQ ID NOs: 1 to 16, and also provides a high-throughput high-uniform sequencing method using the primer set.

Hla 유전자를 위한 pcr 프라이머 세트, 및 이를 이용한 서열 분석 방법

Abstract: 본 발명은 서열번호 1 내지 16 중의 어느 하나에 나타낸 뉴클레오티드 서열로 구성된 프라이머를 포함하는, HLA 유전자 증폭에서 사용하기 위한 프라이머 세트를 제공하고, 상기 프라이머 세트를 사용하는 매우 효율적이고 매우 균일한 서열 분석 방법을 제공한다.